Wnt molecules are a class of cysteine-rich secreted glycoproteins that participate in various developmental events during embryogenesis and adult tissue homeostasis. Since its discovery in 1982, the roles of Wnt signaling have been established in various key regulatory systems in biology. Wnt signals exert pleiotropic effects, including mitogenic stimulation, cell fate specification, and differentiation. The Wnt signaling pathway in humans has been shown to be involved in a wide variety of disorders including colon cancer, sarcoma, coronary artery disease, tetra-amelia, Mullerian duct regression, eye vascular defects, and abnormal bone mass. The canonical Wnt pathway functions by regulating the function of the transcriptional coactivator β-catenin, whereas noncanonical pathways function independent of β-catenin. Although the role of Wnt signaling is well established in epithelial malignancies, its role in mesenchymal tumors is more controversial. Some studies have suggested that Wnt signaling plays a pro-oncogenic role in various sarcomas by driving cell proliferation and motility; however, others have reported that Wnt signaling acts as a tumor suppressor by committing tumor cells to differentiate into a mature lineage. Wnt signaling pathway also plays an important role in regulating cancer stem cell function. In this review, we will discuss Wnt signaling pathway and its role in osteosarcoma.

Liver fibrosis is a common wound-healing response to chronic liver injuries, including alcoholic or drug toxicity, persistent viral infection, and genetic factors. Myofibroblastic transdifferentiation (MTD) is the pivotal event during liver fibrogenesis, and research in the past few years has identified key mediators and molecular mechanisms responsible for MTD of hepatic stellate cells (HSCs). HSCs are undifferentiated cells which play an important role in liver regeneration. Recent evidence demonstrates that HSCs derive from mesoderm and at least in part via septum transversum and mesothelium, and HSCs express markers for different cell types which derive from multipotent mesenchymal progenitors. There is a regulatory commonality between differentiation of adipocytes and that of HSC, and the shift from adipogenic to myogenic or neuronal phenotype characterizes HSC MTD. Central of this shift is a loss of expression of the master adipogenic regulator peroxisome proliferator activated receptor γ (PPARγ). Restored expression of PPARγ and/or other adipogenic transcription genes can reverse myofibroblastic HSCs to differentiated cells. Vertebrate Wnt and Drosophila wingless are homologous genes, and their translated proteins have been shown to participate in the regulation of cell proliferation, cell polarity, cell differentiation, and other biological roles. More recently, Wnt signaling is implicated in human fibrosing diseases, such as pulmonary fibrosis, renal fibrosis, and liver fibrosis. Blocking the canonical Wnt signal pathway with the co-receptor antagonist Dickkopf-1 (DKK1) abrogates these epigenetic repressions and restores the gene PPARγ expression and HSC differentiation. The identified morphogen mediated epigenetic regulation of PPARγ and HSC differentiation also serves as novel therapeutic targets for liver fibrosis and liver regeneration. In conclusion, the Wnt signaling promotes liver fibrosis by enhancing HSC activation and survival, and we herein discuss what we currently know and what we expect will come in this field in the next future.

Liver cancer is the fifth and seventh most common cause of cancer in men and women, respectively. Wnt/β-catenin signalling has emerged as a critical player in both the development of normal liver as well as an oncogenic driver in hepatocellular carcinoma (HCC). Based on the current understanding, this article summarizes the possible mechanisms for the aberrant activation of this pathway with specific focus on HCC. Furthermore, we will discuss the role of dickkopfs (DKKs) in regulating Wnt/β-catenin signalling, which is poorly understood and understudied. DKKs are a family of secreted proteins that comprise at least four members, namely DKK1-DKK4, which act as inhibitors of Wnt/β-catenin signalling. Nevertheless, not all members antagonize Wnt/β-catenin signalling. Their functional significance in hepatocarcinogenesis remains to be further characterized for which these studies should provide new insights into the regulatory role of DKKs in Wnt/β-catenin signalling in hepatic carcinogenesis. Because of the important oncogenic roles, there are an increasing number of therapeutic molecules targeting β-catenin and the Wnt/β-catenin pathway for potential therapy of HCC.